{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:20:20Z","timestamp":1790630420787,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2014,7,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>The molecular mechanism(s) regulating hypoxia-induced vascular fibrosis are unresolved. Hyperaldosteronism correlates positively with vascular remodeling in pulmonary arterial hypertension, suggesting that aldosterone may contribute to the pulmonary vasculopathy of hypoxia. The hypoxia-sensitive transcription factors c-Fos\/c-Jun regulate steroidogenic acute regulatory protein (StAR), which facilitates the rate-limiting step of aldosterone steroidogenesis. We hypothesized that c-Fos\/c-Jun upregulation by hypoxia activates StAR-dependent aldosterone synthesis in human pulmonary artery endothelial cells (HPAECs) to promote vascular fibrosis in pulmonary arterial hypertension.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Patients with pulmonary arterial hypertension, rats with Sugen\/hypoxia\u2013pulmonary arterial hypertension, and mice exposed to chronic hypoxia expressed increased StAR in remodeled pulmonary arterioles, providing a basis for investigating hypoxia\u2013StAR signaling in HPAECs. Hypoxia (2.0% FiO\n                      <jats:sub>2<\/jats:sub>\n                      ) increased aldosterone levels selectively in HPAECs, which was confirmed by liquid chromatography\u2013mass spectrometry. Increased aldosterone by hypoxia resulted from enhanced c-Fos\/c-Jun binding to the proximal activator protein-1 site of the\n                      <jats:italic>StAR<\/jats:italic>\n                      promoter in HPAECs, which increased StAR expression and activity. In HPAECs transfected with StAR\u2013small interfering RNA or treated with the activator protein-1 inhibitor SR-11302 [3-methyl-7-(4-methylphenyl)-9-(2,6,6-trimethylcyclohexen-1-yl)nona-2,4,6,8-tetraenoic acid], hypoxia failed to increase aldosterone, confirming that aldosterone biosynthesis required StAR activation by c-Fos\/c-Jun. The functional consequences of aldosterone were confirmed by pharmacological inhibition of the mineralocorticoid receptor with spironolactone or eplerenone, which attenuated hypoxia-induced upregulation of the fibrogenic protein connective tissue growth factor and collagen III in vitro and decreased pulmonary vascular fibrosis to improve pulmonary hypertension in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion\u2014<\/jats:title>\n                    <jats:p>Our findings identify autonomous aldosterone synthesis in HPAECs attributable to hypoxia-mediated upregulation of StAR as a novel molecular mechanism that promotes pulmonary vascular remodeling and fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.113.007690","type":"journal-article","created":{"date-parts":[[2014,4,28]],"date-time":"2014-04-28T22:14:09Z","timestamp":1398723249000},"page":"168-179","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["Upregulation of Steroidogenic Acute Regulatory Protein by Hypoxia Stimulates Aldosterone Synthesis in Pulmonary Artery Endothelial Cells to Promote Pulmonary Vascular Fibrosis"],"prefix":"10.1161","volume":"130","author":[{"given":"Bradley A.","family":"Maron","sequence":"first","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Oldham","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen Y.","family":"Chan","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara O.","family":"Vargas","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Arons","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Yi","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Loscalzo","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane A.","family":"Leopold","sequence":"additional","affiliation":[{"name":"From the Divisions of Cardiovascular Medicine (B.A.M., S.Y.C., E.A., Y.-Y.Z., J.L., J.A.L.) and Pulmonary and Critical Care Medicine (W.M.O.), Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA; Department of Cardiology, Veterans Affairs Boston Healthcare System, Boston, MA (B.A.M.); and Department of Pathology, Boston Children\u2019s Hospital and Harvard Medical School, Boston, MA (S.O.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2012.158"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/1755-1536-5-S1-S24"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24337"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.108.847707"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00335.2012"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00300.2012"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.112.094722"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurjhf\/hfs173"},{"key":"e_1_3_4_10_2","first-page":"2797","article-title":"Regulation of aldosterone synthase in human vascular endothelial cells by angiotensin II and adrenocorticotropin.","volume":"81","author":"Takeda Y","year":"1996","unstructured":"Takeda Y, Miyamori I, Yoneda T, Hatakeyama H, Inaba S, Furukawa K, Mabuchi H, Takeda R. 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